title: The AKT inhibitor AZD5363 is selectively active in PI3KCA mutant gastric cancer, and sensitizes a patient-derived gastric cancer xenograft model with PTEN loss to Taxotere.
abstract: BACKGROUND
  Activation of the PI3K/AKT pathway is a common phenomenon in cancer due to multiple mechanisms, including mutation of PI3KCA, loss or mutation of PTEN, or over-expression of receptor tyrosine kinases. We recently developed a novel AKT kinase inhibitor, AZD5363, and demonstrated that HGC27, a cell line harboring both PI3KCA mutation and PTEN loss, displayed the greatest sensitivity to this AKT inhibitor in vitro and in vivo.
  To further elucidate the correlation between AZD5363 response and genetic alterations in gastric cancer (GC) and identify GC patients with both PI3KCA mutations and PTEN loss, we investigated the effects of pharmacological inhibition of AKT on a panel of 20 GC cell lines and genetic aberrations in tumor samples from a cohort of Chinese GC patients. We demonstrated that GC cells with PI3KCA mutations were selectively sensitive to AZD5363. Disease linkage studies showed that PI3KCA activating mutations or PTEN loss were found in 2.7% (4/150) and 23% (14/61) of Chinese GC patients respectively. To further dissect the role of PI3KCA mutation and PTEN loss in response to AKT inhibition, we tested the antitumor activity of AZD5363 in two patient-derived GC xenograft (PDGCX) models harboring either PI3KCA mutation or PTEN loss. Our data indicated that AZD5363 monotherapy treatment led to a moderate response in the PI3KCA mutant PDGCX model. Whilst monotherapy AZD5363 or Taxotere were ineffective in the PTEN negative PDGCX model, significant anti-tumor activity was observed when AZD5363 was combined with Taxotere.
  
  
  CONCLUSIONS
  Our results indicated that PI3KCA mutation is an important determinant of response to AKT inhibition in GC and combination with AZD5363 can overcome innate resistance to Taxotere in a PTEN loss PDGCX model. It is suggested that AKT inhibitor is an attractive option for treatment of a new segment of GC patients with aberrant PI3K/AKT signaling.
authors.affiliation: Innovation Center China, AstraZeneca, No, 199 Liangjing Road, Zhangjiang Hi-Tech Park, Shanghai 201203, China. yudehua@yahoo.com.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.forename: Barry R
authors.initials: BR
authors.lastname: Davies
authors.forename: Sufang
authors.initials: S
authors.lastname: Han
authors.forename: Minhua
authors.initials: M
authors.lastname: Zhou
authors.forename: Yu
authors.initials: Y
authors.lastname: Bai
authors.forename: Jingchuan
authors.initials: J
authors.lastname: Zhang
authors.forename: Yan
authors.initials: Y
authors.lastname: Xu
authors.forename: Lily
authors.initials: L
authors.lastname: Tang
authors.forename: Huiying
authors.initials: H
authors.lastname: Wang
authors.forename: Yuan Jie
authors.initials: YJ
authors.lastname: Liu
authors.forename: Xiaolu
authors.initials: X
authors.lastname: Yin
authors.forename: Qunsheng
authors.initials: Q
authors.lastname: Ji
authors.forename: De-Hua
authors.initials: DH
authors.lastname: Yu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use; D044466:Asian People; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002681:China; D004195:Disease Models, Animal; D000077143:Docetaxel; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008819:Mice, Nude; D009154:Mutation / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics*; D051059:PTEN Phosphohydrolase / Q000172:deficiency* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use*; D011758:Pyrroles / Q000494:pharmacology / Q000627:therapeutic use*; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D043823:Taxoids / Q000494:pharmacology / Q000627:therapeutic use*; D014157:Transcription Factors / Q000235:genetics*; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D009687:Nuclear Proteins; C503859:PI3KCA protein, human; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; D043823:Taxoids; D014157:Transcription Factors; D000077143:Docetaxel; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; C575618:capivasertib